1,542 research outputs found

    Effects of Kynurenine Pathway Inhibition on NAD+ Metabolism and Cell Viability in Human Primary Astrocytes and Neurons

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    The kynurenine pathway (KP) is the principle route of L-Tryptophan (TRP) metabolism, producing several neurotoxic and neuroprotective metabolic precursors before complete oxidation to the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). KP inhibition may prove therapeutic in central nervous system (CNS) inflammation by reducing the production of excitotoxins such as quinolinic acid (QUIN). However, KP metabolism may also be cytoprotective through the de novo synthesis of intracellular NAD+. We tested the hypothesis that the KP is directly involved in the maintenance of intracellular NAD+ levels and SIRT1 function in primary astrocytes and neurons through regulation of NAD+ synthesis. Competitive inhibition of indoleamine 2,3 dioxygenase (IDO), and quinolinic acid phosphoribosyltransferase (QPRT) activities with 1-methyl-L-Tryptophan (1-MT), and phthalic acid (PA) respectively, resulted in a dose-dependent decrease in intracellular NAD+ levels and sirtuin deacetylase-1 (SIRT1) activity, and correlated directly with reduced cell viability. These results support the hypothesis that the primary role of KP activation during neuroinflammation is to maintain NAD+ levels through de novo synthesis from TRP. Inhibition of KP metabolism under these conditions can compromise cell viability, NAD-dependent SIRT1 activity and CNS function, unless alternative precursors for NAD+ synthesis are made available

    Microbial Community Composition of Two Environmentally Conserved Estuaries in the Midorikawa River and Shirakawa River

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    To provide a general overview of the microbial communities in environmentally conserved estuaries, the top 5 cm of sediment was sampled from the sandy estuary of the Shirakawa River and from the muddy estuary of the Midorikawa River. Higher amounts of organic matter were detected in the Midorikawa estuary sample than in the Shirakawa estuary sample. Measurement of redox potential revealed that the Shirakawa estuary was aerobic and the Midorikawa estuary was much less aerobic. Clone analysis was performed by targeting partial 16S rRNA gene sequences and using extracted DNA from the samples as a template. Various bacteria were detected, among which Gammaproteobacteria was dominant at both estuaries. Unclassified clones were detected in the Gammaproteobacteria group, mainly among samples from the Midorikawa estuary. Other detected bacterial groups were Alphaproteobacteria, Deltaproteobacteria, Chloroflexi, Actinobacteria, and Bacteroidetes. All the Deltaproteobacteria clones were anaerobic sulfate-reducing bacteria. Those aerobic and anaerobic bacteria coexisted in the top 5 cm of the estuary sediments indicating the surface layer have active sulfur and carbon cycle. Abundance of aerobic Gammaproteobacteria may be an indicator for conserved estuaries

    Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer

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    Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolising enzyme inducing immune tolerance. The present study aimed to investigate IDO expression and its prognostic significance in endometrial cancer. Indoleamine 2,3-dioxygenase expression in endometrial cancer tissues (n=80) was immunohistochemically scored as four groups (IDO−, 1+, 2+, and 3+). The high IDO expression (IDO2+ or 3+) in tumour cells was found in 37 (46.3%) of the 80 cases, and was positively correlated with surgical stage, myometrial invasion, lymph-vascular space involvement, and lymph node metastasis, but not with the histological grade. Patients with high IDO expression had significantly impaired overall survival and progression-free survival (PFS) (P=0.002 and P=0.001, respectively) compared to patients with no or weak expression of IDO (IDO− or 1+). The 5-year PFS for IDO−/1+, 2+, and 3+ were 97.7, 72.9, and 36.4%, respectively. Even in patients with early-stage disease (International Federation of Gynecology and Obstetrics I/II, n=64), the PFS for IDO2+/3+ was significantly poor (P=0.001) compared to that for IDO−/1+. On multivariate analysis, IDO expression was an independent prognostic factor for PFS (P=0.020). These results indicated that the high IDO expression was involved in the progression of endometrial cancer and correlated with the impaired clinical outcome, suggesting that IDO is a novel and reliable prognostic indicator for endometrial cancer

    Brevianes Revisited

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    Breviones are a new family of secondary metabolites that were originally isolated from the New Zealand endemic fungus Penicillium brevicompactum var. Dierckx. These compounds are generally characterized by a new carbon skeleton, known as breviane, which that has three possible structural variations, such as breviane, abeo-breviane, and abeo-norbreviane. Brevianes present a basic diterpenic tricyclic core that is mevalonic in origin and is similar to that of perhydrophenanthrene. The core bears four methyl groups at positions C4, C8, C10, and C13 and has defined stereochemistry at positions C5, C8, C9, C10, and C14. The C1'-C7' side chain has been proposed to have a polyketide biosynthetic origin and is joined to the diterpenic moiety through carbons C2'-C15'. The cyclization and lactonization of this part of the molecule leads to the characteristic breviane spiranic ring fused to the α-pyrone

    Origin of Low-Frequency Negative Transconductance Dispersion in p-HEMT

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    Measurements of low-frequency transconductance dispersion at different temperatures and conductance deep level transient spectroscopic(CDLTS) studies of an AlGaAs/InGaAs pseudomorphic HEMT were carried out. The experimental results show the presence of defect states at the AlGaAs/InGaAs hetero-interface. A mobility degradation model was developed to explain the low frequency negative transconductance dispersion as well as the apparent hole-like peaks observed in the CDLTS spectra. This model incorporates a time dependent change in 2DEG mobility due to ionised impurity scattering by the remaining charge states at the adjoining AlGaAs/InGaAs hetero-interface
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